1. Field of the Invention
The present invention relates to novel opioid receptor antagonists and agonists, methods of making these compounds, and methods of use.
2. Description of the Background
The opioid receptor system has been extensively studied over the past eight decades, driven primarily by a search for analgesics that do not possess the abuse potential associated with morphine. While these studies were unsuccessful, our understanding of the opioid system has increased tremendously. A significant breakthrough in our understanding of this system came about as a realization that the pharmacology of opioids is receptor based. From this vantage point, the focus of research turned to identifying receptor subtypes with the ultimate goal of assigning specific physiological function to individual receptors. Today, the receptor system is known to be composed of the three distinct subtypes OP1, OP2, and OP3 (delta, kappa and mu), as each of these have been cloned and been shown to derive from three different chromosomes. For a discussion of opioid receptors, see Kirk-Othmer Encyclopedia of Chemical Technology, Volume 17, Fourth Edition, 1996, pp. 858-881. There is however less however as to the number of subtypes within each of the main branches and while much has been learned along these lines, the process of assigning function to subtypes is still an area of active investigation.
The opioid receptor system has been extensively studied over the past eight decades driven primarily by a search for analgesics that do not possess the abuse potential associated with morphine. While this effort has been unsuccessful to date, recent studies have highlighted the delta opioid receptor system as holding the greatest potential for success. Principally, agonists acting through the delta opioid receptor have been shown to modulate 4 pain while minimizing many of the side-effects associated with morphine which acts primarily at the mu opioid receptor. These unwanted side-effects include physical dependence, respiratory depression, and gastrointestinal motility problems. These findings have led to a dramatic increase in the research efforts directed toward the production of potent, highly delta receptor selective agonists. The bulk of this effort has been in discovering small molecules as opposed to peptides due to their enhanced stability in vivo and their ability to penetrate the central nervous system.
I.
The discovery of potent, highly receptor-selective opioid pure antagonists has been a goal of medicinal chemists for many years.1,2 As molecular probes, antagonists have served as useful tools in the study of both the structure as well as the physiological functions of the highly complex opioid receptor system. Much has been accomplished as evidenced by the elegant work of Portoghese and coworkers over the past decade which ultimately has led to the discovery of the naltrexone-based kappa and delta receptor subtype-selective antagonists norbinaltorphimine3 (1, nor-BNI) and naltrindole4 (2, NTI), respectively. Following Portoghese""s lead, workers at SmithKline Beecham recently reported that the octahydroisoquinoline (3, SB 205588) was a second-generation, highly potent and selective delta antagonist formally derived from naltrindole fragmentation.5 One specific research aim has been the discovery of opioid receptor selective reversibly binding ligands from the N-substituted (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4a) class of compounds that display pure antagonist activity.6 These compounds will be useful as molecular probes for the opioid receptor as well as potential drug candidates for the treatment of substance abuse and other CNS disorders.7 While mu antagonists have for years been used in drug abuse therapy, recent findings suggest that kappa antagonists could provide a more effective, long-lasting treatment strategy.8 A great variety of N-substituted derivatives of 4a has been prepared, but until the recent demonstration of mu selectivity for 5a,9 none had shown selectivity between the opioid receptor subtypes. Since the pure antagonist activity of these compounds is not dependent on the N-substituent, multiple changes to this part of the molecule would be expected to affect binding affinity and possibly receptor selectivity but not alter its fundamental antagonist character. This feature distinguishes this class of antagonist from the morphone-based compounds, which display pure antagonist behavior only with N-substituents such as allyl or cyclopropylmethyl but not methyl, ethyl, or phenethyl.10 It is currently believed that the N-substituent in 4a interacts with a lipophilic binding domain which has been described as either very large or quite malleable since a multitude of different types of N-substituent changes provided ligands displaying high binding affinity.11 It has also been determined that maximum potency and selectivity for the mu opioid receptor is achieved when the N-substituent incorporates a lipophilic entity (phenyl or cyclohexyl ring) separated from the piperidine nitrogen by three atoms as illustrated by compounds 5a-d.9,11 The synthesis of xcexa-selective compounds remains an important goal.
II.
Derivatives of N-substituted (xc2x1)-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, such as 6 and 7, are known to posses nonselective potent opioid pure antagonist activity.12-16 Early investigations of the phenylpiperidine class of opioid antagonists identified the 3-methyl substituent and its trans relative relationship to the 4-substituent as being both necessary and sufficient to impart antagonist activity to the agonist 4-(3-hydroxyphenyl)piperidine.12 This feature distinguished the phenylpiperidines from the oxymorphones which rely on particular N-substituents (i.e. allyl, cyclopropylmethyl) for expression of opioid antagonist activity.17 Further studies demonstrated that the N-substituent in the phenylpiperidine antagonists controls their potency and efficacy.15 Accordingly, there remains a need for compounds which have similar therapeutic effects as the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, but are based on different structural elements. 
III.
Numerous structural types of opioid agonists have been discovered, and several such as methadone, meperidine, fentanyl, and pentazocine as well as others have become important drugs for the treatment of pain.10 However, there are only a few structural types that show potent, opioid pure antagonist activity.10,7 A resurgence in heroin use in recent years coupled with the demonstrated effectiveness of opioid antagonists for the treatment of other substances of abuse has spurred new interest in the development of novel antagonists for opioid receptors.16 
The oxymorphone-related compounds such as naloxone (8a) and naltrexone (8b), where the antagonist activity is dependent upon the N-substituent, have received considerable attention over the past few decades.10 For example, pioneering studies by Portoghese and coworkers lead to the development of the prototypical kappa and delta opioid receptor antagonists, norbinaltorphimine (1, nor-BNI) and naltrindole (2, NTI). In contrast, the N-substituted trans-3,4-dimethyl-(3-hydroxyphenyl)piperidine (9a-d) class of pure antagonist has received relatively little attention. Studies with the N-methyl analog 9a as well as many other N-substituted analogs such as 9b, 9c (LY255582), and 9d showed that the pure antagonist activity was dependent on the 3-methyl substituent and its trans relative relationship to the 4-methyl substituent on the piperidine ring and, unlike the oxymorphone class, was independent of the nature of the N-substituent.7,16,7,6,3,14 Interestingly, the 3,4-dimethyl cis isomer 9e was found to be a mixed agonist-antagonist. May and coworkers18 reported that 2,9xcex1-dimethyl-5-(3-hydroxyphenyl)morphan (10a), which has the 9-methyl group in a configuration comparable to the cis-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (9e) with the 5-(3-hydroxyphenyl) group locked in an equatorial conformation relative to the piperidine ring in the morphan structure, was a weak but pure antagonist.
Neither 2,9xcex2-dimethyl-5-(3-hydroxyphenyl)morphan (10b) nor 2,4xcex2-dimethyl-5-(3-hydroxyphenyl)morphan (10g) have not been reported, due to a lack of synthetic accessibility to these structural isomers. Accordingly, the successful synthetic preparation of 2,9xcex2-morphans and 2,4xcex2-morphans remains an important goal of in the field opioid receptor-binding compounds. 
IV.
In search of analgesics possessing a reduced side-effect profile relative to morphine, much effort has been expended towards finding opioids which operate via xcex4 or xcexa opioid receptors as opposed to the g opioid receptor which meditates the actions of morphine and its congeners.10 BW373U86 (11)19 and SNC-80 (12)20 represent one class of opioid agonists discovered to be selective for the xcex4 opioid receptor. Due to the lack of a clear opioid message substructure (i.e., a tyramine component similar to the enkephalins), compounds 11 and 12 have been referred to as non-classical opioid ligands.5 The piperazine subunit of 11 and 12 is not commonly found in compounds showing activity at the opioid receptors. In contrast, piperidine ring compounds are found in many different classes of opioids.27 If the internal nitrogen atom in compounds 11 or 12 is transposed with the benzylic carbon, piperidine ring analogs such as 13 would be obtained. Even though there are common structural elements between structures 11 or 12 and 13, the expected difference between in basicity between the piperidinyl amino group of 11 or 12 and the di-phenyl substituted amine of 13 is sufficient such that it cannot be predicted whether similarity to suggest that 13 would interact with opioid receptors similar to 11 or 12. It is also interesting to note that compound 13 has some structural elements in common with cis-3-methylfentanyl (14),21,22 a non-classical opioid ligand selective for the mu opioid receptor. Accordingly, the preparation of compound 13 and related structures remains an important goal. 
References
(1) Dhawan, B. N.; Cesselin, F.; Raghubir, R.; Reisine, T.; Bradley, P. B.; Portoghese, P. S.; Hamon, M. International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol. Rev. 1996, 48, 567-592.
(2) Martin, W. R. The evolution of concepts of opioid receptors. In The Opiate Receptors, Pasternak, G. W. Eds.; Humana Press Inc.: New Jersey, 1988, pp. 3-22.
(3) Portoghese, P. S.; Nagase, H.; Lipkowski, A. W.; Larson, D. L.; Takemori, A. E. Binaltorphimine-related bivalent ligands and their kappa opioid receptor antagonist selectivity [published erratum appears in J. Med. Chem. 1998 Oct;31,(10):2056]. J. Med. Chem. 1988, 31, 836-841.
(4) Portoghese, P. S. An approach to the design of receptor-type-selective non-peptide antagonists of peptidergic receptors: xcex4 opioid antagonists. J. Med. Chem. 1991, 34(6), 1757-1762.
(5) Dondio, G.; Ronzoni, S.; Eggleston, D. S.; Artico, M.; Petrillo, P.; Petrone, G.; Visentin, L.; Farina, C.; Vecchietti, V.; Clarke, G. D. Discovery of a novel class of substituted pyrrolooctahydroisoquinolines as potent and selective xcex4 opioid agonists, based on an extension of the message-address concept. J. Med. Chem. 1997, 40, 3192-3198.
(6) Zimmerman, D. M.; Nickander, R.; Horng, J. S.; Wong, D. T. New structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series. Nature 1978, 275, 332-334.
(7) Zimmerman, D. M.; Leander, J. D. Invited perspective, selective opioid receptor agonists and antagonists: Research tools and potential therapeutic agents. J. Med. Chem. 1990, 33, 895-902.
(8) Rothman, R. B.; Gorelick, D. A.; Eichmiller, P. R.; Hill, B. H.; Norbeck, J.; Liberto, J. G. An open-label study of a functional opioid kappa antagonist in the treatment of opioid dependence. In Problems of drug Dependence, 1997: Proceedings of the 59th Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc., Harris, L. S. Eds.; U. S. Department of Health and Human Services: Rockville, Md., 1997; Vol. 178, pp. 309.
(9) Thomas, J. B.; Mascarella, S. W.; Rothman, R. B.; Partilla, J. S.; Xu, H.; McCullough, K. B.; Dersch, C. M.; Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I. Investigation of the N-substituent conformation governing potency and xcexc receptor subtype-selectivity in (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists. J. Med. Chem. 1998, 41(11), 1980-1990.
(10) Aldrich, J. V. Analgesics. In Burger""s Medicinal Chemistry and Drug Discovery, Wolff, M. E. Eds.; John Wiley and Sons, Inc.: 1996; Vol. 3: Therapeutic Agents.
(11) Mitch, C. H.; Leander, J. D.; Mendelsohn, L. G.; Shaw, W. N.; Wong, D. T.; Cantrell, B. E.; Johnson, B. G.; Reel, J. K.; Snoddy, J. D.; Takemori, A. E.; Zimmerman, D. M. 3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines: Opioid antagonists with potent anorectant activity. J. Med. Chem. 1993, 36(20), 2842-2850.
(12) Zimmerman, D. M.; Smits, S.; Nickander, R. Further investigation of novel 3-methyl-4-phenylpiperidine narcotic antagonists. In Proceedings of the 40th Annual Scientfic Meeting of the Committee on Problems of Drug Dependence, 1978, pp. 237-247.
(13) Zimmerman, D. M.; Smits, S. E.; Hynes, M. D.; Cantrell, B. E.; Leander, J. D.; Mendelsohn, L. G.; Nickander, R. Drug Alcohol Depend. 1985, 14, 381-402.
(14) Mitch, C. H.; Leander, J. D.; Mendelsohn, L. G.; Shaw, W. N.; Wong, D. T.; Zimmerman, D. M.; Gidda, S. J.; Cantrell, B. E.; Scoepp, D. D.; Johnson, B. G.; Leander, J. D. J. Med. Chem. 1994, 37, 2262-2265.
(15) Evans, D. A.; Mitch, C. H.; Thomas, R. C.; Zimmerman, D. M.; Robey, R. L. Application of metalated enamines to alkaloid synthesis. An expedient approach to the synthesis of morphine-based analgesics. J. Am. Chem. Soc. 1980, 102, 5955-5956.
(16) Kreek, M. J. Opiates, opioids and addiction. Mol. Psychiatry 1996, 1(3), 232-254.
(17) Zimmerman, D. M.; Gidda, J. S.; Cantrell, B. E.; Schoepp, D. D.; Johnson, B. G.; Leander, J. D. Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist for the treatment of gastrointestinal motility disorders. J. Med. Chem. 1994, 37(15), 2262-2265.
(18) Awaya, H.; May, E. L.; Aceto, M. D.; Merz, H.; Rogers, M. E.; Harris, L. S. Racemic and optically active 2,9-dimethyl-5-(m-hydroxyphenyl)morphans and pharmacological comparison with the 9-demethyl homologues. J. Med. Chem. 1984, 27, 536-539.
(19) Chang, K. J.; Rigdon, G. C.; Howard, J. L.; McNutt, R. W. A novel potent and selective nonpeptidic delta opioid receptor agonist, BW373U86. J. Pharm. Exp. Ther. 1993, 267, 852-857.
(20) Calderon, S. N.; Rothman, R. B.; Porreca, F.; Flippen-Anderson, J. L.; McNutt, R. W.; Xu, H.; Smith, L. E.; Bilsky, E. J.; Davis, P.; Rice, K. C. Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(aR)-xcex1-(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80): A highly selective, nonpeptide xcex4 opioid receptor agonist. J. Med. Chem. 1994, 37, 2125-2128.
(21) Van Bever, W. F.; Niemegeers, C. J. E.; Janssen, P. A. J. Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-(3-methyl-1-(2-phenylethyl)-4-piperidyl)-N-phenylpropanamide and N-(3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl)-N-phenylpropanamide. J. Med. Chem. 1974, 17(10), 1047-1051.
(22) Xu, H.; Kim, C.-H.; Zhu, Y. C.; Weber, R. J.; Rice, K. C.; Rothman, R. B. (+)-cis-Methylfentanyl and its analogs bind pseudoirreversibly to the mu opioid binding site: Evidence for pseudoallosteric modulation. Neuropharmacology 1991, 30, 455-462.
It is an object of the present invention to provide novel compounds which bind to opioid receptors.
It is another object of the present invention to provide novel compounds which are opioid receptors antagonists that bind with high affinity.
It is another object of the present invention to provide novel opiates that are selective for the kappa receptor as compared to the delta and mu receptors.
It is another object of the present invention to provide novel opiates that are selective for the mu and kappa receptors as compared to the delta receptor.
It is another object of the present invention to provide novel opiates that are selective for the delta receptor as compared to the mu and kappa receptors.
It is another object of the present invention to provide novel opiates that are pure antagonists at the mu, delta and kappa receptors.
It is another object of the present invention to provide methods of making the novel compounds.
It is another object of the present invention to provide methods of treating a variety of disease states with the novel opiate compounds of the present invention.
The objects of the present invention may be accomplished with compounds represented by formula (I), or pharmaceutically acceptable salts thereof: 
where
R1 is hydrogen, an alkyl group, an aryl group, or an aralkyl group;
R2 is hydrogen, an alkyl group, an aryl group, or an alkaryl group; and
R3 is 
each X is, independently, halogen, xe2x80x94OH, xe2x80x94OR, an alkyl group, an aryl group, xe2x80x94NH, xe2x80x94NHR, xe2x80x94N(R)2, xe2x80x94CF3, xe2x80x94CN or xe2x80x94C(O)NH2, xe2x80x94C(O)NHR, or xe2x80x94C(O)N(R)2;
each R is, independently, an alkyl group, an aryl group or an alkaryl group;
n is 0 or an integer from 1 to 5; and
Ra is hydrogen or an alkyl group.
The objects above may also be accomplished with compounds represented by formula 
(II): or pharmaceutically acceptable salts thereof,
where
R1 is an alkyl group or aralkyl group; and
R3, R4, R5, R6 are each, independently, hydrogen, an alkyl group, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94N(R)2, halogen, xe2x80x94OR, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2, or xe2x80x94NHC(O)R;
each R is, independently, an alkyl group, an aryl group, or an alkaryl group; and
R7 is hydrogen or an all group.
The objects of the present invention may be also accomplished with compounds represented by formula (III), or pharmaceutically acceptable salts thereof: 
where
R1 is an alkyl group or an aralkyl group;
R2 is hydrogen, an alkyl group, an aralkyl group, xe2x95x90O, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94N(R)2, xe2x80x94NHC(O)R, xe2x80x94NRC(O)R, xe2x80x94NHC(O)R5, or xe2x80x94NRC(O)R5;
R3 and R4 may be hydrogen or methyl, with the proviso that when R is methyl then R4 is hydrogen and when R3 is hydrogen then R4 is methyl;
each R is, independently, an alkyl group, an aryl group, or an alkaryl group; and
R5 is 
each X is, independently, halogen, xe2x80x94OH, xe2x80x94OR, an alkyl group, an aryl group, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94N(R)2, xe2x80x94CF3, xe2x80x94CN, xe2x80x94C(O)NH2, xe2x80x94C(O)NHR, or xe2x80x94C(O)N(R)2;
each R is, independently, an alkyl group, an aryl group, or an alkaryl group;
n is 0 or an integer from 1 to 5; and
Ra is hydrogen or an alkyl group.
The objects above may be accomplished with compounds represented by formula (IV), or pharmaceutically acceptable salts thereof: 
where
Ra and Rb are each, independently, hydrogen or an alkyl group, or Ra and Rb, together, form a cycloalkyl group;
each X is, independently, an alkyl group;
O is a five- or six-membered aryl or heteroaryl group;
each Z is, independently, an alkyl group, xe2x80x94OH, xe2x80x94OR, halogen, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NH2, xe2x80x94NHR, or xe2x80x94N(R)2;
each R is, independently, an alkyl group, an aryl group, or an alkaryl group;
each W is an alkyl group;
n is 0 or an integer from 1 to 4;
y is 0 or an integer from 1 to 5;
z is 0 an integer from 1 to 8; and
R5 is an alkyl group, alkenyl group, or aralkyl group.